S100A6 stimulates proliferation and migration of colorectal carcinoma cells through activation of the MAPK pathways

Duan,Liang; Wu,Rui; Zou,Zhengyu; Wang,Haiyan; Ye,Liwei; Li,Huan; Yuan,Shimei; Li,Xueru; Zha,He; Sun,Hui; Zhang,Yunyuan; Chen,Xian; Zhou,Lan

doi:10.3892/ijo.2013.2231

S100A6 stimulates proliferation and migration of colorectal carcinoma cells through activation of the MAPK pathways

Authors:
- Liang Duan
- Rui Wu
- Zhengyu Zou
- Haiyan Wang
- Liwei Ye
- Huan Li
- Shimei Yuan
- Xueru Li
- He Zha
- Hui Sun
- Yunyuan Zhang
- Xian Chen
- Lan Zhou
View Affiliations

Affiliations: Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China, Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
Published online on: December 30, 2013 https://doi.org/10.3892/ijo.2013.2231
Pages: 781-790

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The S100A6 protein, a member of the S100 protein family, is overexpressed in many tumors including colorectal carcinoma (CRC). Although recent studies showed that the elevated expression of S100A6 was associated with the stage and lymphatic permeation of CRC, little is known about whether and how S100A6 contributes to CRC development. Here we investigated the S100A6 expression in CRC tissues and cell lines, and explored the molecular mechanisms underlying the role of S100A6 in CRC development by examining cell proliferation and migration in vitro, and tumorigenicity in nude mice. The results show that S100A6 expression was markedly increased in CRC tissues and cell lines compared to normal colon tissues and a normal colon mucosal epithelial cell line, respectively. Recombinant adenovirus-mediated overexpression of S100A6 or treatment with recombinant S100A6 protein in HCT116, a CRC cell line with relative low S100A6 expression, resulted in enhanced cell proliferation and migration, and the mitogen-activated protein kinase (MAPK) activation in vitro, and tumor growth in vivo. Conversely, RNAi-mediated knockdown of S100A6 in LoVo, a CRC cell line with relative high S100A6 expression, resulted in reduced cell proliferation, migration and MAPK activity. S100A6-induced proliferation was partially attenuated by an ERK inhibitor while migration was suppressed by a p38 inhibitor. Taken together, our results suggest that the cellular effects of S100A6 are mediated by the ERK and p38 MAPK pathways, and modulation of these pathways may be employed for CRC prevention and therapy.

View Figures

View References

1.	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar
2.	Meyerhardt JA, Li L, Sanoff HK, Carpenter W IV and Schrag D: Effectiveness of bevacizumab with first-line combination chemotherapy for Medicare patients with stage IV colorectal cancer. J Clin Oncol. 30:608–615. 2012. View Article : Google Scholar : PubMed/NCBI
3.	Kuznicki J and Filipek A: Purification and properties of a novel Ca²⁺-binding protein (10.5 kDa) from Ehrlich-ascites-tumour cells. Biochem J. 247:663–667. 1987.PubMed/NCBI
4.	Lesniak W, Slomnicki LP and Filipek A: S100A6 - new facts and features. Biochem Biophys Res Commun. 390:1087–1092. 2009. View Article : Google Scholar : PubMed/NCBI
5.	Breen EC and Tang K: Calcyclin (S100A6) regulates pulmonary fibroblast proliferation, morphology, and cytoskeletal organization in vitro. J Cell Biochem. 88:848–854. 2003. View Article : Google Scholar : PubMed/NCBI
6.	Hwang R, Lee EJ, Kim MH, et al: Calcyclin, a Ca²⁺ ion-binding protein, contributes to the anabolic effects of simvastatin on bone. J Biol Chem. 279:21239–21247. 2004.
7.	Ohuchida K, Mizumoto K, Ishikawa N, et al: The role of S100A6 in pancreatic cancer development and its clinical implication as a diagnostic marker and therapeutic target. Clin Cancer Res. 11:7785–7793. 2005. View Article : Google Scholar : PubMed/NCBI
8.	Nedjadi T, Kitteringham N, Campbell F, et al: S100A6 binds to annexin 2 in pancreatic cancer cells and promotes pancreatic cancer cell motility. Br J Cancer. 101:1145–1154. 2009. View Article : Google Scholar : PubMed/NCBI
9.	Luo X, Sharff KA, Chen J, He TC and Luu HH: S100A6 expression and function in human osteosarcoma. Clin Orthop Relat Res. 466:2060–2070. 2008. View Article : Google Scholar : PubMed/NCBI
10.	Mbeunkui F, Metge BJ, Shevde LA and Pannell LK: Identification of differentially secreted biomarkers using LC-MS/MS in isogenic cell lines representing a progression of breast cancer. J Proteome Res. 6:2993–3002. 2007. View Article : Google Scholar : PubMed/NCBI
11.	Leclerc E, Fritz G, Weibel M, Heizmann CW and Galichet A: S100B and S100A6 differentially modulate cell survival by interacting with distinct RAGE (receptor for advanced glycation end products) immunoglobulin domains. J Biol Chem. 282:31317–31331. 2007. View Article : Google Scholar : PubMed/NCBI
12.	Donato R: S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles. Int J Biochem Cell Biol. 33:637–668. 2001. View Article : Google Scholar : PubMed/NCBI
13.	Heizmann CW, Fritz G and Schafer BW: S100 proteins: structure, functions and pathology. Front Biosci. 7:d1356–d1368. 2002. View Article : Google Scholar : PubMed/NCBI
14.	Donato R: Intracellular and extracellular roles of S100 proteins. Microsc Res Tech. 60:540–551. 2003. View Article : Google Scholar : PubMed/NCBI
15.	Komatsu K, Andoh A, Ishiguro S, et al: Increased expression of S100A6 (Calcyclin), a calcium-binding protein of the S100 family, in human colorectal adenocarcinomas. Clin Cancer Res. 6:172–177. 2000.PubMed/NCBI
16.	Alvarez-Chaver P, Rodriguez-Pineiro AM, Rodriguez-Berrocal FJ, Martinez-Zorzano VS and Paez de la Cadena M: Identification of hydrophobic proteins as biomarker candidates for colorectal cancer. Int J Biochem Cell Biol. 39:529–540. 2007. View Article : Google Scholar : PubMed/NCBI
17.	Kilanczyk E, Graczyk A, Ostrowska H, Kasacka I, Lesniak W and Filipek A: S100A6 is transcriptionally regulated by beta-catenin and interacts with a novel target, lamin A/C, in colorectal cancer cells. Cell Calcium. 51:470–477. 2012. View Article : Google Scholar : PubMed/NCBI
18.	Fang JY and Richardson BC: The MAPK signalling pathways and colorectal cancer. Lancet Oncol. 6:322–327. 2005. View Article : Google Scholar : PubMed/NCBI
19.	Tothova V and Gibadulinova A: S100P, a peculiar member of S100 family of calcium-binding proteins implicated in cancer. Acta Virol. 57:238–246. 2013. View Article : Google Scholar : PubMed/NCBI
20.	Ghavami S, Rashedi I, Dattilo BM, et al: S100A8/A9 at low concentration promotes tumor cell growth via RAGE ligation and MAP kinase-dependent pathway. J Leukoc Biol. 83:1484–1492. 2008. View Article : Google Scholar : PubMed/NCBI
21.	Kwon CH, Moon HJ, Park HJ, Choi JH and Park do Y: S100A8 and S100A9 promotes invasion and migration through p38 mitogen-activated protein kinase-dependent NF-kappaB activation in gastric cancer cells. Mol Cells. 35:226–234. 2013. View Article : Google Scholar : PubMed/NCBI
22.	Wu R, Duan L, Ye L, et al: S100A9 promotes the proliferation and invasion of HepG2 hepatocellular carcinoma cells via the activation of the MAPK signaling pathway. Int J Oncol. 42:1001–1010. 2013.PubMed/NCBI
23.	Nakashima M, Sakai T, Hiraiwa H, et al: Role of S100A12 in the pathogenesis of osteoarthritis. Biochem Biophys Res Commun. 422:508–514. 2012. View Article : Google Scholar : PubMed/NCBI
24.	Jin Q, Chen H, Luo A, Ding F and Liu Z: S100A14 stimulates cell proliferation and induces cell apoptosis at different concentrations via receptor for advanced glycation end products (RAGE). PloS One. 6:e193752011. View Article : Google Scholar : PubMed/NCBI
25.	Duan L, Wu R, Ye L, et al: S100A8 and S100A9 are associated with colorectal carcinoma progression and contribute to colorectal carcinoma cell survival and migration via Wnt/beta-catenin pathway. PloS One. 8:e620922013. View Article : Google Scholar : PubMed/NCBI
26.	Zou Z, Wang H, Li Y, et al: Prokaryotic expression of recombinant protein HS100A6 and its biological effects on human osteosarcoma cell line 143B. China Biotechnol. 32:1–7. 2012.
27.	He TC, Zhou S, da Costa LT, Yu J, Kinzler KW and Vogelstein B: A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci USA. 95:2509–2514. 1998. View Article : Google Scholar : PubMed/NCBI
28.	Seger R and Krebs EG: The MAPK signaling cascade. FASEB J. 9:726–735. 1995.PubMed/NCBI
29.	Berta GN, Ghezzo F, D’Avolio A, et al: Enhancement of calcyclin gene RNA expression in squamous cell carcinoma of the oral mucosa, but not in benign lesions. J Oral Pathol Med. 26:206–210. 1997. View Article : Google Scholar : PubMed/NCBI
30.	Vimalachandran D, Greenhalf W, Thompson C, et al: High nuclear S100A6 (Calcyclin) is significantly associated with poor survival in pancreatic cancer patients. Cancer Res. 65:3218–3225. 2005.PubMed/NCBI
31.	Yang YQ, Zhang LJ, Dong H, et al: Upregulated expression of S100A6 in human gastric cancer. J Dig Dis. 8:186–193. 2007. View Article : Google Scholar : PubMed/NCBI
32.	Fullen DR, Garrisi AJ, Sanders D and Thomas D: Expression of S100A6 protein in a broad spectrum of cutaneous tumors using tissue microarrays. J Cutan Pathol. 35(Suppl 2): 28–34. 2008. View Article : Google Scholar : PubMed/NCBI
33.	Slomnicki LP and Lesniak W: S100A6 (calcyclin) deficiency induces senescence-like changes in cell cycle, morphology and functional characteristics of mouse NIH 3T3 fibroblasts. J Cell Biochem. 109:576–584. 2010.
34.	Simone C: Signal-dependent control of autophagy and cell death in colorectal cancer cell: the role of the p38 pathway. Autophagy. 3:468–471. 2007. View Article : Google Scholar : PubMed/NCBI
35.	Wei SC, Tsao PN, Weng MT, Cao Z and Wong JM: Flt-1 in colorectal cancer cells is required for the tumor invasive effect of placental growth factor through a p38-MMP9 pathway. J Biomed Sci. 20:392013. View Article : Google Scholar : PubMed/NCBI
36.	Ragusa M, Statello L, Maugeri M, et al: Specific alterations of the microRNA transcriptome and global network structure in colorectal cancer after treatment with MAPK/ERK inhibitors. J Mol Med. 90:1421–1438. 2012. View Article : Google Scholar : PubMed/NCBI
37.	Mohan SK, Gupta AA and Yu C: Interaction of the S100A6 mutant (C3S) with the V domain of the receptor for advanced glycation end products (RAGE). Biochem Biophys Res Commun. 434:328–333. 2013. View Article : Google Scholar : PubMed/NCBI
38.	Heijmans J, Buller NV, Hoff E, et al: Rage signalling promotes intestinal tumourigenesis. Oncogene. 32:1202–1206. 2013. View Article : Google Scholar : PubMed/NCBI
39.	Sasahira T, Akama Y, Fujii K and Kuniyasu H: Expression of receptor for advanced glycation end products and HMGB1/amphoterin in colorectal adenomas. Virchows Arch. 446:411–415. 2005. View Article : Google Scholar : PubMed/NCBI
40.	Kuniyasu H, Chihara Y and Takahashi T: Co-expression of receptor for advanced glycation end products and the ligand amphoterin associates closely with metastasis of colorectal cancer. Oncol Rep. 10:445–448. 2003.PubMed/NCBI
41.	Hofmann MA, Drury S, Fu C, et al: RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell. 97:889–901. 1999. View Article : Google Scholar : PubMed/NCBI
42.	Ichikawa M, Williams R, Wang L, Vogl T and Srikrishna G: S100A8/A9 activate key genes and pathways in colon tumor progression. Mol Cancer Res. 9:133–148. 2011. View Article : Google Scholar : PubMed/NCBI